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AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity

Spatial control of G-protein-coupled receptor (GPCR) signaling, which is used by cells to translate complex information into distinct downstream responses, is achieved by using plasma membrane (PM) and endocytic-derived signaling pathways. The roles of the endomembrane in regulating such pleiotropic...

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Detalles Bibliográficos
Autores principales: Gorvin, Caroline M., Rogers, Angela, Hastoy, Benoit, Tarasov, Andrei I., Frost, Morten, Sposini, Silvia, Inoue, Asuka, Whyte, Michael P., Rorsman, Patrik, Hanyaloglu, Aylin C., Breitwieser, Gerda E., Thakker, Rajesh V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792449/
https://www.ncbi.nlm.nih.gov/pubmed/29420171
http://dx.doi.org/10.1016/j.celrep.2017.12.089
Descripción
Sumario:Spatial control of G-protein-coupled receptor (GPCR) signaling, which is used by cells to translate complex information into distinct downstream responses, is achieved by using plasma membrane (PM) and endocytic-derived signaling pathways. The roles of the endomembrane in regulating such pleiotropic signaling via multiple G-protein pathways remain unknown. Here, we investigated the effects of disease-causing mutations of the adaptor protein-2 σ subunit (AP2σ) on signaling by the class C GPCR calcium-sensing receptor (CaSR). These AP2σ mutations increase CaSR PM expression yet paradoxically reduce CaSR signaling. Hypercalcemia-associated AP2σ mutations reduced CaSR signaling via Gα(q/11) and Gα(i/o) pathways. The mutations also delayed CaSR internalization due to prolonged residency time of CaSR in clathrin structures that impaired or abolished endosomal signaling, which was predominantly mediated by Gα(q/11). Thus, compartmental bias for CaSR-mediated Gα(q/11) endomembrane signaling provides a mechanistic basis for multidimensional GPCR signaling.